Threshold and spectral sensitivity of vision in medaka Oryzias latipes determined by a novel template wave matching method.

We propose a new analytical method for determining the response threshold in electroretinogram (ERG) in which the wave shows a biphasic slow dc-potential shift. This method uses the recorded wave to the highest intensity stimuli in each wavelength tested as a template wave f(t), and it was compared with other recorded waves obtained under lower intensities g(t). Our test recordings in medaka Oryzias latipes were analogous between the template and the compared waveforms, although there were differences in amplitude and time lag (τ, peak time difference) which occurred as a result of the difference in stimulus intensity. Cross-correlation analysis was applied. Based on the obtained cross-correlation function Cfg(τ) in each comparison, τ was determined as the time lag at which the cross-correlation coefficient Rfg(τ) showed the maximum value. Determined thresholds that were based on both the experimenter's visual inspection and this new method agreed well when the adoption condition was set to satisfy R(τ) ≥ 0.7 and τ ≤ 150 ms in scotopic or τ ≤ 120 ms in photopic conditions. We concluded that this "template wave matching method" is a quick and reliable objective assessment that can be used to determine the threshold. This study analyzed ERG recordings in response to 6 kinds of wavelength light stimuli (380 nm to 620 nm) at different photon flux densities. We report the threshold levels and relative spectral sensitivities in scotopic and photopic vision of medaka.

Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence that Aquaporin 9 Acts as an Astrocyte-to-Neuron Lactate Shuttle in Concert with Monocarboxylate Transporters To Support RGC Function and Survival.

Aquaporin 9 (AQP9) is an aquaglyceroporin that can transport lactate. Accumulating evidence suggests that astrocyte-to-neuron lactate shuttle (ANLS) plays a critical role in energy metabolism in neurons, including retinal ganglion cells (RGCs). To test the hypothesis that AQP9, in concert with monocarboxylate transporters (MCTs), participates in ANLS to maintain function and survival of RGCs, Aqp9-null mice and wild-type (WT) littermates were subjected to optic nerve crush (ONC) with or without intravitreal injection of an MCT2 inhibitor. RGC density was similar between the Aqp9-null mice and WT mice without ONC, while ONC resulted in significantly more RGC density reduction in the Aqp9-null mice than in the WT mice at day 7. Positive scotopic threshold response (pSTR) amplitude values were similar between the two groups without ONC, but were significantly more reduced in the Aqp9-null mice than in the WT mice 7days after ONC. MCT2 inhibitor injection accelerated RGC death and pSTR amplitude reduction only in the WT mice with ONC. Immunolabeling revealed that both RGCs and astrocytes expressed AQP9, that ONC predominantly reduced astrocytic AQP9 expression, and that MCTs 1, 2, and 4 were co-localized with AQP9 at the ganglion cell layer. These retinal MCTs were also co-immunoprecipitated with AQP9 in the WT mice. ONC decreased the co-immunoprecipitation of MCTs 1 and 4, but did not impact co-immunoprecipitation of MCT2. Retinal glucose transporter 1 expression was increased in Aqp9-null mice. Aqp9 gene deletion reduced and increased the intraretinal L-lactate and D-glucose concentrations, respectively. Results suggest that AQP9 acts as the ANLS to maintain function and survival of RGCs.

Restoring light sensitivity using tunable near-infrared sensors.

Enabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons, and enabled mice to perform a learned light-driven behavior. We tuned responses to different wavelengths, by using nanorods of different lengths, and to different radiant powers, by using engineered channels with different temperature thresholds. We targeted TRP channels to human retinas, which allowed the postmortem activation of different cell types by near-infrared light.

Pet Dogs with Subclinical Acute Radiodermatitis Experience Widespread Somatosensory Sensitization.

Radiation-induced dermatitis (RID) is a common and painful complication of radiotherapy. When severe, radiation-associated pain (RAP) can reduce the efficacy of radiotherapy by limiting the radiation dose given, and/or necessitating breaks in treatment. Current RAP mitigation strategies are of limited efficacy. Our long-term goal is to develop a comparative oncology model, in which novel analgesic interventions for RAP can be evaluated. The aim of this study was to validate quantitative end points indicative of RAP in pet dogs with subclinical and low-grade RID. Extremity soft tissue sarcomas were treated with post-operative irradiation (54 Gy in 18 fractions). Visual toxicity scores, questionnaire-based pain instruments and objective algometry [mechanical quantitative sensory testing (mQST)], were evaluated regularly. Breed-matched control populations were also evaluated to address the effect of potential confounders. Skin biopsies from within the irradiated field were collected at baseline and after 24 Gy irradiation, for analysis of pain-related genes using the nanoString nCounter platform. Relative to control populations, mechanical thresholds decreased in irradiated test subjects as the total radiation dose increased, with the most pronounced effect at the irradiated site. This was accompanied by increased mRNA expression of GFRα3, TNFα, TRPV2 and TRPV4. In a separate set of dogs with moderate-to-severe RID, serum concentrations of artemin (the ligand for GFRα3) were elevated relative to controls (P = 0.015). Progressive reduction in mechanical thresholds, both locally and remotely, indicates widespread somatosensory sensitization during radiation treatment. mQST in pet dogs undergoing radiation treatment represents an innovative tool for preclinical evaluation of novel analgesics.

Ricco's law and absolute threshold for foveal detection of black holes.

Visual detection of small black objects surrounded by a light background depends on background luminance, pupil size, optical blur, and object size. Holding pupil and optics fixed, we measured the minimum background luminance needed for foveal detection of small black targets as a function of target size. For all three observers, absolute threshold varied inversely with target area when disk diameter subtended less than 10' of visual angle. For target diameter ≥10', threshold remained constant at about 0.3 Td, which was also the absolute threshold for detecting light spots 10' or larger in diameter on a black background. These results are consistent with Ricco's law of spatial summation: a "black hole" is just detectable when the background luminance is sufficiently high for its absence inside the Ricco area to reduce 555 nm photon flux by 7500 photons/s, which is the same change needed to detect light spots on a black surround. These results can be accounted for by a differential pair of Ricco detectors, each about the size of the receptive field center of magocellular retinal ganglion cells when projected into object space through the eye's weakly aberrated optical system. Statistical analysis of the model suggests the quantum fluctuations due to internal, biological noise (i.e., "scotons") are a greater handicap than the photon fluctuations inherent in the light stimulus at absolute foveal threshold.

Oral sensory dysfunction following radiotherapy.

OBJECTIVES/HYPOTHESIS: To assess differences in oral tactile sensation between subjects who have undergone radiation therapy (XRT) compared to healthy controls. STUDY DESIGN: Cross-sectional cohort comparison. METHODS: Thirty-four subjects with a history of XRT were compared with 23 healthy controls. There was no difference in age (P = .23), but there were slightly more males in the XRT cohort (P = .03). The mean (standard deviation) time after XRT completion was 3.84 (4.84) years. Fifty-six percent of the XRT cohort received chemotherapy. Using our previously validated methodology to measure oral tactile sensory threshold quantitatively with Cheung-Bearelly monofilaments, sensory thresholds of four subsites (anterior tongue, buccal mucosa, posterior tongue, soft palate) were compared for the two cohorts. RESULTS: Site-by-site comparisons showed higher forces were required for stimulus detection at all four subsites among subjects in the XRT cohort compared to healthy controls. Mean force in grams for XRT versus control cohorts were: anterior tongue, 0.39 (1.0) versus 0.02 (0.01); buccal mucosa, 0.42 (0.95) versus 0.06 (0.05); posterior tongue, 0.76 (1.46) versus 0.10 (0.07); and soft palate, 0.86 (1.47) versus 0.08 (0.05) (P < .001 for all comparisons). Combining all four subsites into a single metric to assess an overall level of oral tactile dysfunction, the XRT cohort had reduced sensation by 18.7 dB (P < .001). CONCLUSIONS: After radiation therapy, the oral cavity and oropharynx exhibit global tactile sensory dysfunction, manifested by increased tactile forces required for stimulus detection. The magnitude of sensory impairment is 18.7 dB. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:2282-2286, 2017.

Role of extrinsic noise in the sensitivity of the rod pathway: rapid dark adaptation of nocturnal vision in humans.

UNLABELLED: Rod-mediated 500 nm test spots were flashed in Maxwellian view at 5 deg eccentricity, both on steady 10.4 deg fields of intensities (I) from 0.00001 to 1.0 scotopic troland (sc td) and from 0.2 s to 1 s after extinguishing the field. On dim fields, thresholds of tiny (5') tests were proportional to √I (Rose-DeVries law), while thresholds after extinction fell within 0.6 s to the fully dark-adapted absolute threshold. Thresholds of large (1.3 deg) tests were proportional to I (Weber law) and extinction thresholds, to √I. CONCLUSIONS: rod thresholds are elevated by photon-driven noise from dim fields that disappears at field extinction; large spot thresholds are additionally elevated by neural light adaptation proportional to √I. At night, recovery from dimly lit fields is fast, not slow.

Understanding disability glare: light scatter and retinal illuminance as predictors of sensitivity to contrast.

The presence of a bright light in the visual field has two main effects on the retinal image: reduced contrast and increased retinal illuminance because of scattered light; the latter can, under some conditions, lead to an improvement in retinal sensitivity. The combined effect remains poorly understood, particularly at low light levels. A psychophysical flicker-cancellation test was used to measure the amount and angular distribution of scattered light in the eye for 40 observers. Contrast thresholds were measured using a functional contrast sensitivity test. Pupil-plane glare-source illuminances (i.e., 0, 1.35, and 19.21 lm/m2), eccentricities (5°, 10°, and 15°), and background luminances (1, 2.6, and 26 cd/m2) were investigated. Visual performance was better than predicted, based on a loss of retinal image contrast caused by scattered light, particularly in the mesopic range. Prediction accuracy improved significantly when the expected increase in retinal sensitivity in the presence of scattered light was also incorporated in the model.

The effect of simultaneous flickering light stimulation on global form and motion perception thresholds.

The question regarding the exact function of the primary visual cortex (V1) in vision has been around ever since the description of residual vision after damage to this cortical area by Riddoch in 1917. In 2002, Schoenfeld and colleagues proposed that V1 can be saturated by flashes of light, by which the function of V1-bypassing visual pathways can be "unmasked". The Schoenfeld group found that light flashes applied on stimulus onset led to the elevation of brightness increment detection thresholds, but left motion detection thresholds unaltered. Although the proposed method (i.e. the use of light flashes to induce refractoriness in V1) could be a simple, cheap and elegant way of exploring V1 functions, no study has followed up on this. Therefore it is not known if it works at all with other types of stimuli. For that reason, we decided to revisit the idea in a modified form. Global form and motion perception thresholds were assessed with static Glass pattern stimuli and random dot kinematograms, with and without 12Hz flickering light stimulation. Global motion thresholds were almost unaltered by flickering stimulation, while a significant threshold elevation was caused in the global form perception task. The strongest conclusion allowed by our data is that simultaneous flickering photostimulation elevates global form perception thresholds but not global motion perception thresholds. This is in some way related to the refractoriness generated in an unsatisfactorily defined part of V1. We suggest that this does not necessarily reflect the activity of V1-bypassing pathways, and propose that the application of light flashes is a method that deserves more attention in the exploration of the V1-dependent and independent elements of visual consciousness in human subjects.

Short-term effects of neoadjuvant chemoradiation therapy on anorectal function in rectal cancer patients: a pilot study.

BACKGROUND: Neoadjuvant chemoradiation therapy followed by curative surgery has gained acceptance as the therapy of choice in locally advanced rectal cancer. However, deterioration of anorectal function after long-course neoadjuvant chemoradiation therapy combined with surgery for rectal cancer is poorly defined. The aim of this study was to evaluate the physiological and clinical change of anorectal function after neoadjuvant chemoradiation therapy for rectal cancer. METHODS: We analyzed 30 patients on whom preoperative anorectal manometry data were available both before and after chemoradiation from October 2010 to September 2011. All patients underwent long-course neoadjuvant chemoradiation therapy. We compared manometric parameters between before and after neoadjuvant chemoradiation therapy. RESULTS: Of 30 patients, 20 were males and 10 females. The mean age was 64.9 ± 9.9 years (range, 48-82). Before nCRT, the rectal compliance was higher in patients with ulceroinfiltrative type (P = 0.035) and greater involvement of luminal circumference (P = 0.017). However, there was the tendency of increased rectal sensory threshold for desire to defecate when the patient had decreased circumferential ratio of the tumor (P = 0.099), down-graded T stage (P = 0.016), or reduced tumor volume (P = 0.063) after neoadjuvant chemoradiation. CONCLUSIONS: Neoadjuvant chemoradiation therapy did not significantly impair overall sphincter function before radical operation. The relationship between tumor response of chemoradiation and sensory threshold for desire to defecate may suggest that neoadjuvant chemoradiation may be helpful for defecatory function as well as local disease control, at least in the short-term period after the radiation in locally advanced rectal cancer patients.

Mouse ganglion-cell photoreceptors are driven by the most sensitive rod pathway and by both types of cones.

Intrinsically photosensitive retinal ganglion cells (iprgcs) are depolarized by light by two mechanisms: directly, through activation of their photopigment melanopsin; and indirectly through synaptic circuits driven by rods and cones. To learn more about the rod and cone circuits driving ipRGCs, we made multielectrode array (MEA) and patch-clamp recordings in wildtype and genetically modified mice. Rod-driven ON inputs to ipRGCs proved to be as sensitive as any reaching the conventional ganglion cells. These signals presumably pass in part through the primary rod pathway, involving rod bipolar cells and AII amacrine cells coupled to ON cone bipolar cells through gap junctions. Consistent with this interpretation, the sensitive rod ON input to ipRGCs was eliminated by pharmacological or genetic disruption of gap junctions, as previously reported for conventional ganglion cells. A presumptive cone input was also detectable as a brisk, synaptically mediated ON response that persisted after disruption of rod ON pathways. This was roughly three log units less sensitive than the rod input. Spectral analysis revealed that both types of cones, the M- and S-cones, contribute to this response and that both cone types drive ON responses. This contrasts with the blue-OFF, yellow-ON chromatic opponency reported in primate ipRGCs. The cone-mediated response was surprisingly persistent during steady illumination, echoing the tonic nature of both the rod input to ipRGCs and their intrinsic, melanopsin-based phototransduction. These synaptic inputs greatly expand the dynamic range and spectral bandpass of the non-image-forming visual functions for which ipRGCs provide the principal retinal input.

Intense focused ultrasound can reliably induce sensations in human test subjects in a manner correlated with the density of their mechanoreceptors.

Sensations generated by intense focused ultrasound (iFU) can occur cutaneously and/or at depth, in contrast to other forms of stimulation (e.g., heat, electricity), whose action usually occurs only at the skin surface, or mechanical stimulation (e.g., von Frey hairs, calibrated forceps, tourniquets) that compress and thus stimulate all tissue. Previous work on iFU stimulation has led to the hypothesis that the tactile basis of iFU stimulation should correlate with the density of mechanoreceptors at the site of iFU stimulation. Here we tested that hypothesis, correlating a "two-point" neurological examination-a standard measure of superficial mechanoreceptor density-with the intensity of superficially applied iFU necessary to generate sensations with high sensitivity and specificity. We applied iFU at 1.1 MHz for 0.1 s to the fingertip pads of 17 test subjects in a blinded fashion and escalated intensities until they consistently observed iFU-induced sensations. Most test subjects achieved high values of sensitivity and specificity, doing so at values of spatially and temporally averaged intensity measuring <100 W/cm(2). Moreover, the test subjects' sensitivity to iFU stimulation correlated with the density of mechanoreceptors as determined by a standard two-point discrimination neurological examination, consistent with earlier hypotheses.

Comparison of LEP and QST and their contribution to standard sensory diagnostic assessment of spinal lesions: a pilot study.

This study evaluates the additional use of laser-evoked potentials (LEP) and quantitative sensory testing (QST) in the sensory assessment of spinal lesions. Four consecutive patients with spinal lesions verified by MRI and clinical evidence for mild spinothalamic tract involvement were included. The electrophysiological workup [somatosensory evoked potentials (SEP) and LEP] was compared to QST. Electrophysiology and QST were reassessed after about 6 months. LEP detected impaired spinothalamic tract function in 7/8 examinations. QST pointed to spinothalamic tract lesions by loss of thermal function (3/8); most frequent positive sensory signs (3/8) were paradoxical heat sensations. LEP and QST results were concordant in 6/8 examinations. SEPs were abnormal in 2/8 examinations. Congruent results between SEP and both LEP and QST were obtained in 3/8 examinations. LEP detected more deficits than any single QST parameter or their combination but additional QST allows the detection of positive sensory signs. The diagnostic gain of SEP was limited.

Laser modulation of heat and capsaicin receptor TRPV1 leads to thermal antinociception.

Er,Cr:YSGG lasers are used clinically in dentistry. The advantages of laser therapy include minimal thermal damage and the alleviation of pain. This study examined whether the Er,Cr:YSGG laser has in vivo and in vitro antinociceptive effects in itself. In capsaicin-evoked acute licking/shaking tests and Hargreaves tests, laser irradiation with an aerated water spray suppressed nociceptive behavior in mice. Laser irradiation attenuated TRPV1 activation by capsaicin in Ca(2+) imaging experiments with TRPV1-overexpressing cells and cultured trigeminal neurons. Therefore, the laser-induced behavioral changes are probably due to the loss of TRPV1 activity. TRPV4 activity was also attenuated, but limited mechanical antinociception by the laser was observed. The laser failed to alter the other receptor functions, which indicates that the antinociceptive effect of the laser is dependent on TRPV1. These results suggest that the Er,Cr:YSGG laser has analgesic effects via TRPV1 inhibition. Such mechanistic approaches may help define the laser-sensitive pain modality and increase its beneficial uses.

Similar effects of repetitive transcranial magnetic stimulation of MT+ and a dorsomedial extrastriate site including V3A on pattern detection and position discrimination of rotating and radial motion patterns.

Our recent psychophysical experiments have identified differences in the spatial summation characteristics of pattern detection and position discrimination tasks performed with rotating, expanding, and contracting stimuli. Areas MT and MST are well established to be involved in processing these stimuli. fMRI results have shown retinotopic activation of area V3A depending on the location of the center of radial motion in vision. This suggests the possibility that V3A may be involved in position discrimination tasks with these motion patterns. Here we use repetitive transcranial magnetic stimulation (rTMS) over MT+ and a dorsomedial extrastriate region including V3A to try to distinguish between TMS effects on pattern detection and position discrimination tasks. If V3A were involved in position discrimination, we would expect to see effects on position discrimination tasks, but not pattern detection tasks, with rTMS over this dorsomedial extrastriate region. In fact, we could not dissociate TMS effects on the two tasks, suggesting that they are performed by the same extrastriate area, in MT+.

Phosphene thresholds evoked with single and double TMS pulses.

OBJECTIVE: To evaluate the quantitative advantage of double pulses vs. single pulses in TMS phosphenes evoked from the occipital cortex. METHODS: In 10 healthy subjects single pulse thresholds were compared with thresholds from double pulses of equal strength at a stimulus onset asynchrony (SOA) of 2, 5, 10, and 20ms, both with biphasic and monophasic pulse forms. In a second experiment fusion time, i.e. the double pulse SOA where the percept passes from one into two phosphenes was determined. RESULTS: Thresholds obtained with double pulses did not depend on SOA. They were lowered to about 90% of single pulse thresholds. Biphasic pulses yielded lower thresholds (89%) than monophasic pulses. Fusion time was about 45ms but highly varied inter-individually and did not depend on stimulation intensity. CONCLUSIONS: Although double pulses are more efficient compared to single pulses the advantage is rather small. Previous recommendations to apply double pulses in phosphene studies cannot be confirmed, at least for SOAs up to 20ms. The independence of fusion time to stimulus intensity indicates a non-linear relation between network activity and the percept of phosphene persistence. SIGNIFICANCE: Phosphene threshold studies do not gain advantages by the application of double pulses.

Reduction of type II taste cells correlates with taste dysfunction after X-ray irradiation in mice.

BACKGROUND: Taste dysfunction that develops after radiotherapy for head and neck cancer impairs patients' quality of life. Although taste cells have been shown to degenerate after exposure to X-ray irradiation, the alteration in taste cell population is unclear. This study investigated the histopathological change of taste bud structure and the taste cell population in X-ray irradiated mice. METHODS: The head and neck region of C57BL/6J male mice was exposed to a single 15 Gy dose of X-ray irradiation and a chronological histopathological analysis of the circumvallate papilla was performed. Preference for sweet taste was measured using the two-bottle preference method. RESULTS: The histological analysis of the circumvallate papilla revealed that the basal cells had almost disappeared, but that there was not clear change in the spindle-shaped taste cells on day 4 after irradiation. The number of taste cells had decreased on day 8, and then remained unchanged until day 20, after which they increased and recovered to their original number by day 24. There was a more marked decrease in the number of alpha-gustducin-positive type II taste cells than in the number of serotonin-positive type III taste cells. Preference for sweet taste measured by the two-bottle preference method was decreased in parallel with taste cell number. CONCLUSION: These findings suggest that X-ray irradiation disrupts the basal cells, resulting in a decrease of the number of taste cells, particularly type II taste cells, which may be the cause of radiotherapy-induced taste dysfunction.

Visual performance with sport-tinted contact lenses in natural sunlight.

PURPOSE: The use of tinted and clear contact lenses (CLs) in all aspects of life is becoming a more popular occurrence, particularly in athletic activities. This study broadens previous research regarding performance-tinted CLs and their effects on measures of visual performance. METHODS: Thirty-three subjects (14 male, 19 female) were fitted with clear B&L Optima 38, 50% visible light transmission Amber and 36% visible light transmission Gray-Green Nike Maxsight CLs in an individualized randomized sequence. Subjects were dark-adapted with welding goggles before testing and in between subtests involving a Bailey-Lovie chart and the Haynes Distance Rock test. The sequence of testing was repeated for each lens modality. RESULTS: The Amber and Gray-Green lenses enabled subjects to recover vision faster in bright sunlight compared with clear lenses. Also, subjects were able to achieve better visual recognition in bright sunlight when compared with clear lenses. Additionally, the lenses allowed the subjects to alternate fixation between a bright and shaded target at a more rapid rate in bright sunlight as compared with clear lenses. Subjects preferred both the Amber and Gray-Green lenses over clear lenses in the bright and shadowed target conditions. CONCLUSIONS: The results of the current study show that Maxsight Amber and Gray-Green lenses provide better contrast discrimination in bright sunlight, better contrast discrimination when alternating between bright and shaded target conditions, better speed of visual recovery in bright sunlight, and better overall visual performance in bright and shaded target conditions compared with clear lenses.

Combined optical and electrical stimulation of neural tissue in vivo.

Low-intensity, pulsed infrared light provides a novel nerve stimulation modality that avoids the limitations of traditional electrical methods such as necessity of contact, presence of a stimulation artifact, and relatively poor spatial precision. Infrared neural stimulation (INS) is, however, limited by a 2:1 ratio of threshold radiant exposures for damage to that for stimulation. We have shown that this ratio is increased to nearly 6:1 by combining the infrared pulse with a subthreshold electrical stimulus. Our results indicate a nonlinear relationship between the subthreshold depolarizing electrical stimulus and additional optical energy required to reach stimulation threshold. The change in optical threshold decreases linearly as the delay between the electrical and optical pulses is increased. We have shown that the high spatial precision of INS is maintained for this combined stimulation modality. Results of this study will facilitate the development of applications for infrared neural stimulation, as well as target the efforts to uncover the mechanism by which infrared light activates neural tissue.